Selective Retention of β-Carbolines and 7,12-Dimethylbenz[ a ]anthracene in the Brain [Elektronisk resurs] Role of Neuromelanin and Cytochrome P450 for Toxicity

• The ß-carbolines norharman and harman structurally resemble the synthetic compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that is known for its ability to damage neuromelanin-containing dopaminergic neurons of the substantia nigra and thereby induce parkinsonism. MPTP is, however, not normally present in the environment whereas the ß-carbolines are present in cooked food and tobacco smoke. In this thesis it was demonstrated that norharman and harman had affinity to melanin and were retained in neuromelanin-containing neurons of frogs up to 30 days post-injection (the longest survival time examined). It was also demonstrated that norharman induced neurodegeneration, activation of glia cells and motor impairment in mice. Furthermore, this compound induced ER stress and cell death in PC12 cells. An in vitro model of dopamine melanin-loaded PC12 cells was developed in order to study the effect of melanin on norharman-induced toxicity. In this model, melanin seemed to attenuate toxicity induced by low concentrations of norharman. After exposure to the highest concentration of norharman, melanin clusters were disaggregated and there was an increased expression of stress proteins and caspases-3, known to be involved in apoptosis. The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz[ a ]anthracene was demonstrated to have a CYP1A1-dependent localization in endothelial cells in the choroid plexus, in the veins in the leptomeninges and in the cerebral veins of mice pre-treated with CYP1-inducers. These results demonstrate that the distribution of environmental compounds could be influenced by the presence of neuromelanin and expression of CYP enzymes in the brain and that norharman may induce neurotoxic effects in vivo and in vitro. 

Ämnesord

Medical and Health Sciences  (hsv)

Basic Medicine  (hsv)

Pharmacology and Toxicology  (hsv)

Medicin och hälsovetenskap  (hsv)

Medicinska och farmaceutiska grundvetenskaper  (hsv)

Farmakologi och toxikologi  (hsv)

PHARMACY  (svep)

Toxicology  (svep)

FARMACI  (svep)

Toxikologi  (svep)

Toxicology  (uu)

toxikologi  (uu)

Genre

government publication  (marcgt)

Indexterm och SAB-rubrik

Toxicology

β-carboline

neuromelanin

norharman

harman

parkinsonism

Parkinson's disease

motoric impairment

behaviour

glia cells

substantia nigra

dopamine melanin

PC12 cells

ER stress

grp78

hsp90

cytochrome P450

CYP1A1

CYP1B1

blood-brain interfaces

7,12-dimethylbenz[a]anthracene

polycyclic aromatic hydrocarbon

endothelial cell

smooth muscle cell

bioactivation

Toxikologi